We are studying neurochemical abnormalities in genetically obese-diabetic mice. We are trying to determine the relationship of the elevated hypothalamic norepinephrine levels found obob and dbdb mice to the hyperphagia and diabetes expressed by the mutations. We have found resistance to the amine-depleting effects of reserpine in obob mice, but not dbdb mice, suggesting a difference in the neurochemical nature of the norepinephrine excess in these mutations. Also we have found that amphetamine treatment can normalize food intake, hypothalamic norepinephrine levels, and blood glucose levels in obob mice. These results suggest the possibility of an abnormal norepinephrine release mechanism in obob mice, and we are currently studying this possibility in hypothalamic tissue suspensions. We also intend to study release phenomenon in the dbdb mice. Other parameters being studied in these models include serotonin, epinephrine and dopamine systems; receptor systems such as alpha-adrenergic and dopaminergic receptors; the effects of manipulation of catecholamine systems on the expression of the obesity; and drug effects on food intake and neurochemistry in the obese-diabetic mice.